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      Clinical, Virologic, Immunologic Outcomes and Emerging HIV Drug Resistance Patterns in Children and Adolescents in Public ART Care in Zimbabwe

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          Abstract

          Objective

          To determine immunologic, virologic outcomes and drug resistance among children and adolescents receiving care during routine programmatic implementation in a low-income country.

          Methods

          A cross-sectional evaluation with collection of clinical and laboratory data for children (0-<10 years) and adolescents (10–19 years) attending a public ART program in Harare providing care for pediatric patients since 2004, was conducted. Longitudinal data for each participant was obtained from the clinic based medical record.

          Results

          Data from 599 children and adolescents was evaluated. The participants presented to care with low CD4 cell count and CD4%, median baseline CD4% was lower in adolescents compared with children (11.0% vs. 15.0%, p<0.0001). The median age at ART initiation was 8.0 years (IQR 3.0, 12.0); median time on ART was 2.9 years (IQR 1.7, 4.5). On ART, median CD4% improved for all age groups but remained below 25%. Older age (≥ 5 years) at ART initiation was associated with severe stunting (HAZ <-2: 53.3% vs. 28.4%, p<0.0001). Virologic failure rate was 30.6% and associated with age at ART initiation. In children, nevirapine based ART regimen was associated with a 3-fold increased risk of failure (AOR: 3.5; 95% CI: 1.3, 9.1, p = 0.0180). Children (<10y) on ART for ≥4 years had higher failure rates than those on ART for <4 years (39.6% vs. 23.9%, p = 0.0239). In those initiating ART as adolescents, each additional year in age above 10 years at the time of ART initiation (AOR 0.4 95%CI: 0.1, 0.9, p = 0.0324), and each additional year on ART (AOR 0.4, 95%CI 0.2, 0.9, p = 0.0379) were associated with decreased risk of virologic failure. Drug resistance was evident in 67.6% of sequenced virus isolates.

          Conclusions

          During routine programmatic implementation of HIV care for children and adolescents, delayed age at ART initiation has long-term implications on immunologic recovery, growth and virologic outcomes.

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          Most cited references21

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          Long-term consequences of stunting in early life.

          Kathryn Dewey, Khadija Begum (2011)
          This review summarizes the impact of stunting, highlights recent research findings, discusses policy and programme implications and identifies research priorities. There is growing evidence of the connections between slow growth in height early in life and impaired health and educational and economic performance later in life. Recent research findings, including follow-up of an intervention trial in Guatemala, indicate that stunting can have long-term effects on cognitive development, school achievement, economic productivity in adulthood and maternal reproductive outcomes. This evidence has contributed to the growing scientific consensus that tackling childhood stunting is a high priority for reducing the global burden of disease and for fostering economic development. Follow-up of randomized intervention trials is needed in other regions to add to the findings of the Guatemala trial. Further research is also needed to: understand the pathways by which prevention of stunting can have long-term effects; identify the pathways through which the non-genetic transmission of nutritional effects is mediated in future generations; and determine the impact of interventions focused on linear growth in early life on chronic disease risk in adulthood. © 2011 Blackwell Publishing Ltd.
          Article 0 comments Cited 335 times – based on 0 reviews     Review now
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            Growing up with HIV: children, adolescents, and young adults with perinatally acquired HIV infection.

            Rohan Hazra, George K Siberry, Lynne M Mofenson (2010)
            Tremendous success in the prevention and treatment of pediatric HIV in high-resource countries has changed the face of the epidemic. A perinatally HIV-infected child now faces a chronic disease rather than a progressive, fatal one. However, these successes pose new challenges as perinatally HIV-infected youth survive into adulthood. These include maintaining adherence to long-term, likely life-long therapy; selecting successive antiretroviral drug regimens, given the limited availability of pediatric formulations and the lack of pharmacokinetic and safety data in children; and overcoming extensive drug resistance in multi-drug-experienced children. Pediatric HIV care now focuses on morbidity related to long-term HIV infection and its treatment. Survival into adulthood of perinatally HIV-infected youth in high-resource countries encourages expansion of pediatric treatment programs in low-resource countries, where most HIV-infected children live, and provides important lessons about how the epidemic changes with increasing access to antiretroviral therapy for children.
            Article 0 comments Cited 53 times – based on 0 reviews     Review now
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              Antiretroviral therapy responses among children attending a large public clinic in Soweto, South Africa.

              T U Meyers, Marcel Yotebieng, Harry Moultrie … (2011)
              Antiretroviral therapy (ART) access with successful outcomes for children is expanding in resource-limited countries. The aim of this study was to determine treatment responses of children in a routine setting where first-line therapy with lopinavir/ritonavir is routinely included for young children. Outpatient records of children who initiated ART between April 2004 and March 2008 at a government clinic in Soweto were reviewed. Children <3 years initiated ART with lopinavir/ritonavir and those ≥ 3 years initiated with efavirenz-containing regimens. ART was initiated at a median age of 4.3 years, 28.6% also received tuberculosis treatment. During 3155 child-years of follow-up (median follow-up 17 months), 132 children (6%) died giving a mortality rate of 4.2 (95% confidence interval: 3.5, 5.0) deaths per 100 child-years. By 12 and 24 months, 84% and 96% of children achieved virologic suppression. The proportion of children with viral rebound increased from 5.4% to 16.3% at 24 and 36 months from start of ART. Younger children (receiving lopinavir/ritonavir-based first-line therapy) with higher viral loads suppressed more slowly and were more likely to die. Children who were started on treatment for tuberculosis at the time of viral suppression were more likely to have virologic rebound. Despite good treatment outcomes overall, children with advanced disease at ART initiation had poorer outcomes, particularly those <3 years of age, most of whom were treated with lopinavir/ritonavir-containing therapy. The increasing risk of viral rebound over time for the whole cohort is concerning, given currently limited available treatment options for children.
              Article 0 comments Cited 33 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Nicolas Sluis-Cremer: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 14 December 2015
                Publication date Collection: 2015
                Volume: 10
                Issue: 12
                Electronic Location Identifier: e0144057
                Affiliations
                [1 ]Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America
                [2 ]John Snow Inc, Boston, Massachusetts, United States of America
                [3 ]Department of Medicine, University of Zimbabwe College of Health Sciences, Harare, Zimbabwe
                [4 ]Department of Pediatrics, University of Zimbabwe College of Health Sciences, Harare, Zimbabwe
                [5 ]HIV Pathogenesis Program, University of Kwa-Zulu Natal, Durban, South Africa
                [6 ]African Institute of Biomedical Sciences, Harare, Zimbabwe
                [7 ]United States Agency for International Development (USAID), Washington, DC, United States of America
                University of Pittsburgh, UNITED STATES
                Author notes

                Competing Interests: The authors have the following interests: Authors Molly Higgins-Biddle and Bisola Ojikutu are employees of John Snow Inc. A. Tariro Makadzange has served as a consultant on the grant. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

                Conceived and designed the experiments: ATM CEN. Performed the experiments: ATM BC MG GMH TM CEN. Analyzed the data: ATM MH-B RB GMH TM CEN. Contributed reagents/materials/analysis tools: ATM TN BDW BO BP AA CEN CM. Wrote the paper: ATM MH-B BO MBD JvD CEN.

                Article
                Publisher ID: PONE-D-15-42505
                DOI: 10.1371/journal.pone.0144057
                PMC ID: 4678607
                PubMed ID: 26658814
                SO-VID: b0357ed7-1243-4cca-8d2e-7a650da0008d
                License:

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication

                History
                Date received : 28 September 2015
                Date accepted : 12 November 2015
                Page count
                Figures: 2, Tables: 4, Pages: 18
                Funding
                This research has been supported by the President's Emergency Plan for AIDS Relief (PEPFAR) through the U.S. Agency for International Development under the terms of contract no. GHH-I-00–07–00059–00, with the contractor as John Snow Inc. The University of Zimbabwe College of Health Sciences was a sub-grantee with Professor Chiratidzo Ndhlovu as the Principal Investigator. USAID funding supported salaries for research personnel, consultant fees, reagents and supplies for the conduct of the proposed study. John Snow Inc. employees who were involved in the study were Molly Higgins-Biddle and Bisola Ojikutu. Molly Higgins-Biddle provided statistical support for the study during the period of data analysis. Dr. Bisola Ojikutu was the Senior Technical Advisor for JSI. Molly Higgins-Biddle was involved in the data analysis, and both were involved with the review of the manuscript. USAID employees Benjamin Phelps and Anouk Amzel provided technical support to the granting agency but were not involved in the study design, data collection, analysis, decision to publish or preparation of the manuscript. In summary the funder (USAID) provided support in the form of salaries through JSI for some of the authors (MH-B and BO), consultant fees (ATM) and University of Zimbabwe research staff. The funder did not have any additional role in study design, data collection or the decision to publish. The specific roles of the authors are articulated in the ‘author contributions’ section.
                Categories
                Subject: Research Article
                Custom metadata
                Data Availability All relevant data are within the paper and its Supporting Information files, however if additional data is required data will be made available from the Institutional Data Access/Ethic Committee for researchers who meet the criteria for access.

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